The invention relates to epothilone compounds that are useful for the treatment of cancer and other conditions characterized by undesireable cellular proliferation. More particularly, the invention relates to 10,11-dehydroepothilones.
Epothilone A (R=H) and Epothilone B (R=CH3) are produced by Sorangium cellulosum strain So ce 90, the structures of which are shown below, and were the first of several epothilones to be isolated, synthesized, and characterized. Hxc3x6fle et al., 1996, Angew. Chem. Int. Ed. Engl. 35(13/14): 1567-1569. 
Epothilone A and epothilone B possess many of the advantageous properties of paclitaxel (Taxol(copyright), Bristol-Myers Squibb). As a result, there is significant interest in these and structurally related compounds as potential chemotherapeutic agents. The desoxy counterparts of epothilones A and B are known as epothilone C(R=H) and epothilone D(R=CH3), and exhibit similar anti-tumor activity but with less cytotoxicity. The structures of epothilones C and D are shown below. 
Although other naturally occurring epothilones have been described, these compounds are produced in exceedingly small amounts. PCT publication WO 99/65913 describes 39 naturally occurring epothilones obtained from Sorangium cellulosum So ce 90 of which epothilones A, B, C, and D together account for approximately 98.9% of the total epothilones produced. The 35 other naturally occurring epothilone compounds together account for the remaining 1.1% and include epothilone C6 (which may also be referred to as 10,11-dehydroepothilone C) and whose structure is shown below 
The naturally occurring epothilones can be modified through semisynthesis. PCT publication WO 99/27890 describes conversion of epothilones A and B into their lactam analogs. PCT publication WO 99/54318 describes conversion of epothilones C and D into their 12,13-cyclopropane analogs.
Additional epothilone analogs may be produced through de novo synthesis. PCT publications WO 99/07692 and WO 00/00485 describe a synthetic route wherein the methyl group at C-6 is replaced by other aliphatic groups and unsaturation may be introduced at the 10,11-position. PCT publication WO 99/02514 describes total synthesis of lactam analogs of epothilones.
Due to the increasing interest in epothilones as anti-cancer agents, novel derivatives of these compounds are needed and desired to more fully develop their therapeutic potential. The present invention fulfils this need.
This invention relates to epothilone compounds that are useful for the treatment of cancer and other conditions characterized by undesireable cellular proliferation. More particularly, the invention relates to 10,11-dehydroepothilones.
In one aspect, the present invention provides a compound of the formula 
known herein as 10,11-dehydroepothilone D.
In another aspect, the present invention provides compounds of the formula (I) 
wherein:
R1, R2, and R3, are each independently H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, aryl, xe2x80x94C(=O)R6, xe2x80x94C(=O)OR6, or xe2x80x94NR6R7 where R6 and R7 are each independently hydrogen, C1-C5 aliphatic, aryl or alkylaryl;
R5 is H, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
W is O, NR8 where R8 is hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
X is O, CH2 or a carbon-carbon bond;
Y is absent or a C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 alkynyl; and
Ar is aryl; provided that when W is O at least one of R1, R3, or R5 is other than H.
In one embodiment, the present invention provides compounds of the formula (II) 
wherein:
R1, R2, and R3, are each independently H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, aryl, xe2x80x94C(=O)R6, xe2x80x94C(=O)OR6, or xe2x80x94NR6R7 where R6 and R7 are each independently hydrogen, C1-C5 aliphatic, aryl or alkylaryl;
R5 is H, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
W is NR8 where R8 is hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
X is O, CH2 or a carbon-carbon bond;
Y is absent or a C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 alkynyl; and
Ar is aryl.
In one embodiment of the invention, compounds of formula (III) are provided 
wherein:
R1, R2, and R3, are each independently H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, aryl, xe2x80x94C(=O)R6, xe2x80x94C(=O)OR6, or xe2x80x94NR6R7 where R6 and R7 are each independently hydrogen, C1-C5 aliphatic, aryl or alkylaryl;
R5 is H, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, or C2-C5 alkynyl;
R8 is H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, C1-C5 fluoroalkyl, or C1-C5 aminoalkyl.
In another embodiment of the invention, compounds of formula (III) are provided wherein:
R1, R2, and R3 are each independently H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or alkylaryl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, or C1-C5 haloalkyl;
R5 is H, C1-C5 alkyl, or C1-C5 alkoxy;
R8 is hydrogen or C1-C5 alkyl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In one embodiment of the invention, compounds of formula (III) are provided wherein:
R1 and R3 are methyl;
R2 is H;
R4 is H, methyl, ethyl, fluoromethyl, or hydroxymethyl;
R5 is H, methyl, ethyl, or methoxy;
R8 is hydrogen or methyl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of formula (IV) are provided 
wherein:
R1, R2, and R3 are each independently hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or alkylaryl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, or C1-C5 haloalkyl;
R5 is H, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, or C2-C5 alkynyl;
R8 is hydrogen or C1-C5 alkyl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of formula (IV) are provided wherein:
R1 and R3are H;
R2 is methyl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, or C1-C5 haloalkyl;
R5 is H, C1-C5 alkyl, or C1-C5 alkoxy;
R8 is hydrogen or C1-C5 alkyl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of formula (IV) are provided wherein:
R1 and R3 are H;
R2 is methyl;
R4 is H, methyl, ethyl, fluoromethyl, or hydroxymethyl;
R5 is H, methyl, ethyl, or methoxy;
R8 is hydrogen or methyl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of the formulas 
are provided.
In another embodiment of the invention, the compound having the formula 
is provided.
In one embodiment, the present invention provides compounds of the formula (V) 
wherein:
R1, R2, and R3, are each independently H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, aryl, xe2x80x94C(=O)R6, xe2x80x94C(=O)OR6, or N6R7 where R6 and R7 are each independently hydrogen, C1-C5 aliphatic, aryl or alkylaryl;
R5 is C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
W is O;
X is O, CH2 or a carbon-carbon bond;
Y is absent or a C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 alkynyl; and
Ar is aryl.
In one embodiment of the invention, compounds of formula (VI) are provided 
wherein:
R1, R2, and R3, are each independently H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, aryl, xe2x80x94C(=O)R6, xe2x80x94C(=O)OR6, or xe2x80x94NR6R7 where R6 and R7 are each independently hydrogen, C1-C5 aliphatic, aryl or alkylaryl;
R5 is C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, or C2-C5 alkynyl;
R8 is H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl or alkylaryl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, C1-C5 fluoroalkyl, or C1-C5 aminoalkyl.
In another embodiment of the invention, compounds of formula (VI) are provided wherein:
R1, R2, and R3 are each independently H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or alkylaryl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, or C1-C5 haloalkyl;
R5 is C1-C5 alkyl, or C1-C5 alkoxy;
R8 is hydrogen or C1-C5 alkyl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In one embodiment of the invention, compounds of formula (VI) are provided wherein:
R1 and R3 are methyl;
R2 is H;
R4 is H, methyl, ethyl, fluoromethyl, or hydroxymethyl;
R5 is methyl, ethyl, or methoxy;
R8 is hydrogen or methyl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of formula (VII) are provided 
wherein:
R1, R2, and R3 are each independently hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or alkylaryl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, or C1-C5 haloalkyl;
R5 is C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, or C2-C5 alkynyl;
R8 is hydrogen or C1-C5 alkyl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of formula (VII) are provided wherein:
R1 and R3 are H;
R2 is methyl;
R4 is H, C1-C5 alkyl, C1-C5 hydroxyalkyl, or C1-C5 haloalkyl;
R5 is C1-C5 alkyl, or C1-C5 alkoxy;
R8 is hydrogen or C1-C5 alkyl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of formula (VII) are provided wherein:
R1 and R3 are H;
R2 is methyl;
R4 is H, methyl, ethyl, fluoromethyl, or hydroxymethyl;
R5 is methyl, ethyl, or methoxy;
R8 is hydrogen or methyl;
X is O, CH2 or a carbon-carbon bond; and
R9 is selected from the group consisting of 
where Z is O or S, and R10 is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of the formulas 
are provided.
In another embodiment of the invention, the compoundhaving the formula 
is provided.
In another aspect of the present invention, methods for preparing the inventive compounds are provided. In one embodiment, certain of the inventive compounds are prepared by total synthesis. In another embodiment, certain of the inventive compounds are prepared by fermentation of genetically engineered organisms. In another embodiment, certain of the inventive compounds are prepared by chemical transformations performed on compounds prepared by fermentation of genetically engineered organisms. In another embodiment, certain of the inventive compounds are prepared by microbial transformations performed on compounds prepared by fermentation of genetically engineered organisms.
In another aspect of the invention, formulations comprising one or more of the inventive compounds are provided. In one embodiment, the inventive compound or compounds constitute the active principle of the formulation. In another embodiment, the inventive compounds are combined with other active compounds, such as cytotoxic agents and synergists.
In another aspect of the present invention, methods for treating a disease or condition with the inventive compounds are provided. In one embodiment, the inventive compounds are used for treating a disease or condition characterized by cellular hyperproliferation in a subject. In one embodiment, the disease is cancer, including but not limited to cancers of the head and neck, liver or biliary tree, intestine, ovary, lung, central nervous system, lymphatic system, or sarcomas. In another embodiment, the condition is psoriasis, multiple sclerosis, rheumatoid arthritis, or atherosclerosis. In another embodiment, the condition is stenosis or restenosis.
Statements regarding the scope of the present invention and definitions of terms used herein are listed below. The definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
Unless stereochemistry is specifically indicated, all stereoisomers of the inventive compounds are included within the scope of the invention, as pure compounds as well as mixtures thereof.
Some of the crystalline forms for the compounds may exist as polymorphs and as such are included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also encompassed within the scope of this invention.
Protected forms of the inventive compounds are included within the scope of the present invention. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley and Sons, New York (1999), which is incorporated herein by reference in its entirety. For example, a hydroxy protected form of the inventive compounds are those where at least one of the hydroxyl groups is protected by a hydroxy protecting group. Illustrative hydroxy protecting groups include but not limited to tetrahydropyranyl; benzyl; methylthiomethyl; ethylthiomethyl; pivaloyl; phenylsulfonyl; triphenylmethyl; trisubstituted silyl such as trimethyl silyl, triethylsilyl, tributylsilyl, tri-isopropylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl, methyldiphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl and the like; acyl and aroyl such as acetyl, pivaloylbenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl and aliphatic acylaryl and the like. Keto groups in the inventive compounds may similarly be protected.
The present invention includes within its scope prodrugs of the compounds shown herein. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a subject in need thereof. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, H. Bundgaard ed., Elsevier, 1985.
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal, preferably a mammal, that has been the object of treatment, observation or experiment, and most preferably refers to a human whom has been the object of treatment and/or observation.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
The term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is a salt of an inventive compound. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound of the invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like.
The term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d is a medium that is used to prepare a desired dosage form of the inventive compound. A pharmaceutically acceptable carrier includes solvents, diluents, or other liquid vehicle; dispersion or suspension aids; surface active agents; isotonic agents; thickening or emulsifying agents, preservatives; solid binders; lubricants and the like. Remington""s Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) and Handbook of Pharmaceutical Excipients, Third Edition, A. H. Kibbe, ed. (Amer. Pharmaceutical Assoc. 2000), both of which are incorporated herein by reference in their entireties, disclose various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
As used herein, the term xe2x80x9caliphaticxe2x80x9c refers to saturated and unsaturated straight chained, branched chain, cyclic, or polycyclic hydrocarbons that may be optionally substituted at one or more positions. Illustrative examples of aliphatic groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain saturated hydrocarbon substituent. xe2x80x9cAlkenylxe2x80x9d refers to a straight or branched chain hydrocarbon substituent with at least one carbon-carbon double bond. xe2x80x9cAlkynylxe2x80x9d refers to a straight or branched chain hydrocarbon substituent with at least one carbon-carbon triple bound.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or polycyclic groups having at least one aromatic ring structure that optionally include one or more heteroatoms and preferably include three to fourteen carbon atoms. Aryl substituents may optionally be substituted at one or more positions. Illustrative examples of aryl groups include but are not limited to: furanyl, imidazolyl, indanyl, indenyl, indolyl, isooxazolyl, isoquinolinyl, naphthyl, oxazolyl, oxadiazolyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, quinolyl, quinoxalyl, tetrahydronaphththyl, tetrazolyl, thiazolyl, thienyl, benzothiazolyl, and the like.
The aliphatic (i.e., alkyl, alkenyl, etc.) and aryl moieties may be optionally substituted with one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, and most preferably from one to two substituents. The definition of any substituent or variable at a particular location in a molecule is independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein. Examples of suitable substituents include but are not limited to: alkyl, alkenyl, alkynyl, aryl, halo; trifluoromethyl; trifluoromethoxy; hydroxy; alkoxy; cycloalkoxy; heterocyclooxy; oxo; alkanoyl (xe2x80x94C(=O)-alkyl which is also referred to as xe2x80x9cacylxe2x80x9d)); aryloxy; alkanoyloxy; amino; alkylamino; arylamino; aralkylamino; cycloalkylamino; heterocycloamino; disubstituted amines in which the two amino substituents are selected from alkyl, aryl, or aralkyl; alkanoylamino; aroylamino; aralkanoylamino; substituted alkanoylamino; substituted arylamino; substituted aralkanoylamino; thiol; alkylthio; arylthio; aralkylthio; cycloalkylthio; heterocyclothio; alkylthiono; arylthiono; aralkylthiono; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; sulfonamido (e.g., SO2NH2); substituted sulfonamido; nitro; cyano; carboxy; carbamyl (e.g., CONH2); substituted carbamyl (e.g., xe2x80x94C(=O)NRRxe2x80x2 where R and Rxe2x80x2 are each independently hydrogen, alkyl, aryl, aralkyl and the like); alkoxycarbonyl, aryl, substituted aryl, guanidino, and heterocyclo such as indoyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where applicable, the substituent may be further substituted such as with, alkyl, alkoxy, aryl, aralkyl, halogen, hydroxy and the like.
The terms xe2x80x9calkylarylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d refer to an aryl group with an aliphatic substituent that is bonded to the compound through the aliphatic group. An illustrative example of an alkylaryl or arylalkyl group is benzyl, a phenyl with a methyl group that is bonded to the compound through the methyl group (xe2x80x94CH2Ph where Ph is phenyl).
The term xe2x80x9calkoxyxe2x80x9d refers to xe2x80x94OR wherein O is oxygen and R is an aliphatic group.
The term xe2x80x9caminoalkylxe2x80x9d refers to xe2x80x94RNH2 where R is an aliphatic moiety.
The terms xe2x80x9chalogen,xe2x80x9d xe2x80x9chaloxe2x80x9d, or xe2x80x9chalidexe2x80x9d refer to fluorine, chlorine, bromine and iodine.
The term xe2x80x9chaloalkylxe2x80x9d refers to xe2x80x94RX where R is an aliphatic moiety and X is one or more halogens.
The term xe2x80x9chydroxyalkylxe2x80x9d refers to xe2x80x94ROH where R is an aliphatic moiety.
The term xe2x80x9coxoxe2x80x9d refers to a carbonyl oxygen (=O).
In addition to the explicit substitutions at the above-described groups, the inventive compounds may include other substitutions where applicable. For example, the lactone or lactam backbone or backbone substituents may be additionally substituted (e.g., by replacing one of the hydrogens or by derivatizing a non-hydrogen group) with one or more substituents such as C1-C5 aliphatic, C1-C5 alkoxy, aryl, or a functional group. Illustrative examples of suitable functional groups include but are not limited to: acetal, alcohol, aldehyde, amide, amine, boronate, carbamate, carboalkoxy, carbonate, carbodiimide, carboxylic acid, cyanohydrin, disulfide, enamine, ester, ether, halogen, hydrazide, hydrazone, imide, imido, imine, isocyanate, ketal, ketone, nitro, oxime, phosphine, phosphonate, phosphonic acid, quatemary ammonium, sulfenyl, sulfide, sulfone, sulfonic acid, thiol, and the like.
The term xe2x80x9cpurified,xe2x80x9d as used in reference to a compound of the present invention, means that the compound is in a preparation in which the compound forms a major component of the composition, such as constituting about 50%, about 60%, about 70%, about 80%, about 90%, about 95% or more by weight of the components in the composition.